Administration of pharmaceutically active ingredients to the skin or mucosal tissues is known, both to treat local symptoms and to treat systemic disorders. Such dermal application is a desirable alternative to oral administration because, especially with regard to local symptoms, dermal application allows higher doses of the active ingredients to be administered in the location they are most needed. The same high dose level often cannot be given orally due to the digestive system becoming upset from the high level of active ingredient, and because of toxicity problems with higher oral doses for most active ingredients. Thus, oral administration may require low doses and can be less effective than direct transdermal administration.
A difficulty with transdermal administration is that normal skin is relatively impermeable to most pharmaceutically active ingredients. Thus, it is often necessary to use pharmaceutically acceptable carriers to enhance the percutaneous absorption of the active ingredient.
An additional problem related to transdermal administration of active ingredients is that the pharmaceutically acceptable carrier may result in such rapid absorption of the active ingredient in the body of the patient that the active ingredient is too rapidly dissipated within the body to be effective over any period of time. Thus, repeated applications are necessary. Alternatively, the use of bulky and uncomfortable patches may be necessary in order to provide prolonged dermal exposure to the composition containing the active ingredients.
U.S. Pat. No. 2,431,558 (Huber) discloses the use of esters of nicotinic acid as vasodilators. The nicotinic acid esters may be applied to the skin of humans or animals as a composition in solution with mineral, vegetable or animal oils or greases, or emulsions thereof.
U.S. Pat. No. 5,128,376 (Saito et al.) relates to the percutaneous administration of a physiological active agent in a carrier system comprising at least one adjuvant, at least one solvent and at least one diol and/or triol moderator. The large list of possible suitable solvents at col. 4, line 37 to col. 5, line 35 includes amide solvents. The reference does not disclose the use of hydroxy alkyl amides.
Japanese Patent Application 60-228,423 (Tamura et al.) discloses a carrier composition for external drug application comprising azulene, camazulene or guaiazulene and a specific polar compound that exhibits improved permeation and absorption of drugs into the skin. Among the many suitable polar compounds are listed amide compounds. There is no disclosure of the use of the amide compounds without one of the azulene compounds, nor is there is any suggestion that hydroxy alkyl amides are a superior carrier of drugs.
U.S. Pat. Nos. 3,742,951, 3,797,494, and 3,996,934 (all to Zaffaroni) relate to controlled administration of active drugs by the use of bandages having reservoirs containing the drug and wall members for controlling the rate of drug release to the skin. The drug can be used alone in the reservoir or in combination with a carrier or a transport agent. The transport agents are disclosed to aid or assist the drug delivery device to achieve the administration of a drug to a drug receptor. The broad list of transport agents include N,N-di(lower) alkylacetamides including N-(2-hydroxyethyl) acetamide, but there is no teaching or suggestion of the superiority of such transport agents over other carriers or transport agents.
U.S. Pat. No. 4,014,334 (Theeuwes et al.) discloses a laminated osmotic dispensing system for delivery of a beneficial agent. The system is preferably oral, but dermal application is also disclosed. The beneficial agent in the dispensing system may be in the form of a solution, but there is no disclosure of any suitable solvents or carriers.
U.S. Pat. No. 4,573,996 (Kwiatek) relates to a device for administration of an active agent to a host by transdermal means. The active agent may be present either alone or in combination with other active agents and/or a pharmaceutically acceptable carrier or transporting agent. The list of transporting agents includes N,N-di(lower alkyl) acetamides and N-(2-hydroxyethyl) acetamide.
U.S. Pat. Nos. 4,913,905 and 5,128,124 (both to Fankhauser et al.) relate to a transdermal delivery system for administration of oestrogens and gestagens. The active agent in the reservoir of the system is used in combination with a penetration enhancer. N-2-hydroxyethyl acetamide is disclosed as a penetration enhancer, but alkanols are preferred. No benefits from the use of N-2-hydroxyethyl acetamide are disclosed or suggested.
U.S. Pat. No. 5,032,403 (Sinnreich) discloses a multilayer transdermal therapeutic system for the administration of active substances. The reservoir contains the active agent along with a penetrating agent that may be N,N-di-lower-alkylacetamide or N-2-hydroxyethyl acetamide, among others. No benefit from the use of N-2-hydroxyethyl acetamide is disclosed or suggested.
None of the above references discloses or suggests any benefit from the use of hydroxy alkyl amides as a carrier material for a pharmaceutically active agent to be transdermally administered. The references merely equate all of the large number of known carrier materials with each other in terms of effectiveness.